Project description:BackgroundClinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers.MethodsOverall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al. for BC risk discrimination in female BRCA1/2 PV carriers were employed for PRS computation in a curated sample of 295 women of European descent carrying PVs in the BRCA1 (n=183) or the BRCA2 gene (n=112), and did either fulfill the ED criteria (n=162, mean age at diagnosis: 28.3 years, range: 20 to 34 years) or the LD criteria (n=133). Binomial logistic regression was applied to assess the association of standardized PRSs with either ED or LD under adjustment for patient recruitment criteria for germline testing and localization of BRCA1/2 PVs in the corresponding BC or ovarian cancer (OC) cluster regions.ResultsFor BRCA1 PV carriers, the standardized overall BC PRS displayed the strongest association with ED (odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.16-2.31, p<0.01). Additionally, statistically significant associations of selection for the patient recruitment criteria for germline testing and localization of pathogenic PVs outside the BRCA1 OC cluster region with ED were observed. For BRCA2 PV carriers, the standardized PRS for ER-negative BC displayed the strongest association (OR = 2.27, 95% CI: 1.45-3.78, p<0.001).ConclusionsPRSs contribute to the development of extreme phenotypes of female BRCA1/2 PV carriers with respect to age at primary BC diagnosis. Construction of optimized PRS SNP sets for BC risk stratification in BRCA1/2 PV carriers should be the task of future studies with larger, well-defined study samples. Furthermore, our results provide further evidence, that localization of PVs in BC/OC cluster regions might be considered in BC risk calculations for unaffected BRCA1/2 PV carriers.

Project description:INTRODUCTION: Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. METHODS: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. RESULTS: We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. CONCLUSIONS: We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.

Project description:BackgroundGenome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.MethodsWe constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.ResultsThe PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.ConclusionsBC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Project description:Introduction: CHEK2 is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about two fold. We pursued to investigate gene copy number aberrations and gene expression profiles that are typical for breast tumors of CHEK2 1100delC mutation carriers. Materials and methods: A total of 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array comparative genomic hybridization (aCGH) and gene expression experiments (GEX). After dimensionality reduction with CGHregions R package, CHEK2 1100delC associated regions in the aCGH data were detected by Wilcoxon rank sum test. Linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by Bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2 and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3 and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors nominating them as candidates for CHEK2 1100delC associated tumor progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM and LRP1 on 12q13. Altogether 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44 lowered expression levels. Our results suggest WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions we have identified potential drivers of CHEK2 1100delC associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of CHEK2 1100delC mutation. 78 samples from breast tumors: 13 tumors from CHEK2 1100delC mutation carriers, 65 other tumors

Project description:Introduction: CHEK2 is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about two fold. We pursued to investigate gene copy number aberrations and gene expression profiles that are typical for breast tumors of CHEK2 1100delC mutation carriers. Materials and methods: A total of 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array comparative genomic hybridization (aCGH) and gene expression experiments (GEX). After dimensionality reduction with CGHregions R package, CHEK2 1100delC associated regions in the aCGH data were detected by Wilcoxon rank sum test. Linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by Bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2 and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3 and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors nominating them as candidates for CHEK2 1100delC associated tumor progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM and LRP1 on 12q13. Altogether 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44 lowered expression levels. Our results suggest WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions we have identified potential drivers of CHEK2 1100delC associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of CHEK2 1100delC mutation.

Project description:Introduction: CHEK2 is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about two fold. We pursued to investigate gene copy number aberrations and gene expression profiles that are typical for breast tumors of CHEK2 1100delC mutation carriers. Materials and methods: A total of 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array comparative genomic hybridization (aCGH) and gene expression experiments (GEX). After dimensionality reduction with CGHregions R package, CHEK2 1100delC associated regions in the aCGH data were detected by Wilcoxon rank sum test. Linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by Bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2 and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3 and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors nominating them as candidates for CHEK2 1100delC associated tumor progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM and LRP1 on 12q13. Altogether 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44 lowered expression levels. Our results suggest WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions we have identified potential drivers of CHEK2 1100delC associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of CHEK2 1100delC mutation. 78 samples from breast tumors: 13 tumors from CHEK2 1100delC mutation carriers, 65 other tumors

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Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.

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Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.

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